Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding.
Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding.
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DOI：
10.1126/sciimmunol.abc2728
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发表时间：
2020-07-17
影响因子：
24.8
通讯作者：
Vignali DAA
中科院分区：
文献类型：
--
作者：
Andrews LP;Somasundaram A;Moskovitz JM;Szymczak-Workman AL;Liu C;Cillo AR;Lin H;Normolle DP;Moynihan KD;Taniuchi I;Irvine DJ;Kirkwood JM;Lipson EJ;Ferris RL;Bruno TC;Workman CJ;Vignali DAA
对癌症免疫疗法的抗性机制仍然知之甚少。淋巴细胞活化基因-3（LAG 3）信号传导由解整合素和金属蛋白酶-10（ADAM 10）和ADAM 17介导的细胞表面脱落调节。在这里，我们表明，表达金属蛋白酶抗性，不可切割的LAG 3突变体（LAG 3 NC）的小鼠对PD 1阻断具有抗性，并且未能产生有效的抗肿瘤免疫应答。LAG 3 NC的表达本质上扰乱了CD 4 + T常规（Tconv）细胞，限制了它们提供CD 8 + T细胞帮助的能力。此外，这些观察结果的翻译相关性突出显示为头颈部鳞状细胞癌（HNSCC）患者外周血中CD 4 + Tconv细胞上LAG 3高表达和ADAM 10低表达之间的负相关性，这与不良预后相对应。这种相关性也在皮肤癌患者队列中观察到，并且与标准护理免疫治疗后疾病进展增加有关。这些数据表明，LAG 3抑制性受体信号传导的细微变化可以作为一种耐药机制，对患者对免疫疗法的反应性具有实质性影响。
Mechanisms of resistance to cancer immunotherapy remain poorly understood. Lymphocyte Activation Gene-3 (LAG3) signaling is regulated by A Disintegrin And Metalloprotease-10 (ADAM10) and ADAM17-mediated cell surface shedding. Here we show that mice expressing a metalloprotease-resistant, non-cleavable LAG3 mutant (LAG3NC) are resistant to PD1 blockade and fail to mount an effective anti-tumor immune response. Expression of LAG3NC intrinsically perturbs CD4+ T conventional (Tconv) cells, limiting their capacity to provide CD8+ T cell help. Furthermore, the translational relevance for these observations is highlighted with an inverse correlation between high LAG3 and low ADAM10 expression on CD4+ Tconv cells in the peripheral blood of patients with head and neck squamous cell carcinoma (HNSCC), which corresponded with poor prognosis. This correlation was also observed in a cohort of patients with skin cancers, and was associated with increased disease progression after standard-of-care immunotherapy. These data suggest that subtle changes in LAG3 inhibitory receptor signaling can act as a resistance mechanism with a substantive effect on patient responsiveness to immunotherapy.
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